Despite the utility of nicotine replacement therapies and sustained-release bupropion for the treatment of nicotine dependence, there is still a significant proportion of cigarette smokers who are unable to quit smoking, and thus new and effective pharmacotherapies for smoking cessation are needed. Dopamine plays a critical role in nicotine reinforcement, and monoamine oxidase B (MAO-B) inhibitors, which preferentially inhibit dopamine metabolism, may have utility for smoking cessation. In support of this hypothesis, in preliminary studies, we have shown that the selective MAO-B inhibitor selegiline hydrochloride (10 mg/day) significantly increases smoking abstinence rates compared to placebo. This R01 re-submission proposes to study n=200 nicotine dependent cigarette smokers in a randomized, double-blind, placebo-controlled trial to determine the efficacy of selegiline for smoking cessation. Subjects would be inducted onto 10 mg/day of selegiline (5 mg po bid) or placebo (twice daily) over a two-week period prior to the target quit date on trial Day 15. All smokers would receive manualized brief weekly individual smoking cessation counseling. The primary smoking cessation outcome measure will be 7-day point prevalence smoking abstinence at the 6-month follow-up, and secondary cessation outcome measures will include continuous smoking abstinence during the last four weeks of the trial (Days 29-56) and 7-day point prevalence abstinence at the end of the 8-week trial (Days 49-56). Other secondary treatment outcome measures will include retention in the trial, nicotine withdrawal and craving, body weight, depressive symptoms, and selegiline study medication adherence using MEMS technology and detection of urinary selegiline metabolites. Data analysis will focus on an intention-to-treat sample and will utilize Odds Ratios and logistic regression analyses to determine the effects of selegiline on cessation outcomes, and hierarchical linear models (HLM) for continuous outcomes (e.g., craving and withdrawal, weight, depressive symptoms). We predict that selegiline will be superior to placebo, and will lead to greater suppression of tobacco craving and withdrawal. Positive results from this trial would add further support for the safety and efficacy of selegiline for the treatment of nicotine dependence.